Retinoid receptors and other members of this superfamily of nuclear receptors, which include the steroid, thyroid and vitamin D hormone receptors and other “orphan” receptors without known ligands, are new targets for drug development (1). It is thought that retinoic acid (RA) and synthetic retinoids act as ligand-dependent transcription factors with different members of nuclear retinoid receptors to control gene transcription responsible for cellular proliferation, differentiation, development and cell death (2). Two classes of nuclear retinoid receptors (RARs and RXRs) have been identified so far, and each has several different subtypes (α, β, γ). Both (all-E)- and (9Z)-RA bind to RARs and activate transcription mediated by RAR/RXR heterodimers, but (9Z)-RA is the most potent retinoic acid isomer for the RXRs that mediate transcription by forming homodimers or heterodimers.
Recent advances in chemotherapy and chemoprevention have heightened interest in the use of retinoids for preventing or treating several types of cancer, and major therapeutic successes have been demonstrated with retinoids in certain leukemias (3). (all-E)-RA treatment of patients with acute promyelocytic leukemia (APL) leads to a 90% complete remission rate in these patients by inducing normal maturation and apoptosis of APL myeloblasts to neutrophils, but this differentiation therapy is transient and is commonly followed by relapse within 3-15 months, probably due to the development of resistance to retinoic acid (4). (13Z)-RA effectively controls the excessive myeloproliferation in up to 50% of children with juvenile myelomonocytic leukemia (JMML) (5). However, this treatment is not curative and at best can lead to a period of prolonged stabilization of disease, but ultimately patients need to undergo allogenic bone marrow transplantation (4, 6).
All-trans-retinoic acid (ATRA) is the first example of a FDA-approved agent used for differentiation therapy (rather than standard cytotoxic cancer chemotherapy) of patients with APL. Even though it has been shown to be highly effective in APL treatment, clinical resistance occurs frequently with pharmacological doses of ATRA and APL patients often relapse (4). In order to provide more effective therapies, new highly active retinoids need to be identified in the expectation that lower doses of these agents would not induce resistance as rapidly as ATRA.
Some of the most promising retinoids in cancer prevention are 9cRA and related analogs that bind to RXRs. When 9cRA is added to the diet of rats, the number of N-methyl-N-nitrosourea (MNU)-induced mammary cancers was reduced by 92% (30). Because of excessive toxicity, however, the usefulness of 9cRA for chemoprevention of cancer in the human is limited (31-33). To increase the therapeutic index, considerable effort has been devoted toward synthesis of RXR-selective analogs of 9cRA (34, 35). Our laboratory has described the synthesis of several such retinoids and showed that these compounds were effective for the prevention of skin tumors and had lower toxicity than natural retinoids (36). Subsequently, we reported the synthesis of 9cUAB30 which is a selective agonist for the RXRs (37). We have recently shown that this retinoid is comparable in the chemopreventive efficacy of mammary cancers to 9cRA, but it is less toxic (Atigadda et al. J. Med. Chem., 2003).
Tamoxifen, an estrogen antagonist, was the first drug approved by the Federal Drug Administration for breast cancer prevention. This agent and other selective estrogen receptor modulators (SERMs) have been evaluated as a major therapeutic modality in various stages of breast cancer (38). Anti-estrogen therapy, however, is not without risks and limitations; thus, new cancer chemopreventive agents that are effective and non-toxic are needed.
It would be desirable to produce retinoids in high yield and stereoselectivity. For example, retinoids generally possess multiple carbon-carbon double bonds with either cis or trans stereochemistry. Thus, one retinoid can have several stereoisomers depending upon the number of carbon-carbon double bonds. Although synthetic routes to retinoids have been developed, they do not produce retinoids in high yield and stereoselectivity. The methods described herein address this need.